The long-term objective of this project is to increase our understanding of the fundamental features of the metabolism and biologic effects of fluoride with special emphasis on the influence of acid-base status. During the first 12 years of this project, it has been learned that urinary pH is a major determinant of the rate of fluoride removal from the body. The distribution of fluoride between the major fluid compartments of the body has been found to be a function of the magnitude and direction of transmembrane pH gradients. Other studies have clarified the mechanism of fluoride absorption from the GI tract, provided evidence against the concept of fluoride homeostasis and new insights into the effect of growth and development on the pharmacokinetics of fluoride. The proposed studies for the next grant period deal with several aspects of fluoride metabolism and disturbances in amelogenesis. It has been found that hypobaric hypoxia (simulated high altitude) increases the retention of fluoride and that it causes disturbances in enamel mineralization that resemble fluorosis. The physiologic basis of these effects will be studied with emphasis on renal function, the metabolism of calcium, phosphorus and fluoride and the characteristics of calcified tissues. The hypothesis that the mineralization defects caused by hypobaric hypoxia and fluoride share the same basic mechanism will undergo initial testing. It has also been learned that acidosis produced by chronic ammonium chloride administration is associated with defects in enamel mineralization. It is not clear whether the defects are caused by acidosis per se or by elevated levels of ammonium ion. Experiments are proposed to identify the etiologic factor. Several aspects of the metabolism and toxicity of MFP will be studied and compared to those of sodium fluoride. This and toxicity of MFP will be studied and compared to those of sodium fluoride. This research is timely and of clinical importance because of the increasingly widespread use of MFP in dentistry and medicine. Finally, the use of a novel lucite chamber will permit highly controlled studies of the effects of sodium fluoride or MFP on the structure and function of the gastric mucosa, a target organ for the adverse effects of fluoride. The cytoprotectant PGE2 and the inhibitor of prostaglandin synthesis, indomethacin, will be used in these studies to more fully understand the underlying mechanism and possibly suggest new approaches to prevent or reduce the unwanted side effects.